In the manufacture of pharmaceutical products, the active pharmaceutical agent is combined with the desired excipients, diluents and other adjuvant materials in a liquid environment and granulated by conventional techniques to produce active drug granules of a size suitable for incorporation in the desired finished product. For tablet products, for example, a granule size of from 10 to 40 mesh may be preferred. In tabletting, the granules are metered into a tablet press and compressed under high pressures to form a cohesive tablet having a certain required degree of physical integrity, surface smoothness, and other physical properties known to the art. The resulting tablet can then be film- or enteric-coated if desired to provide the desired color, flavor, mouthfeel, bioavailability, resistance to abrasion, etc.
Controlled delivery of drugs from pharmaceutical tablets frequently involves the use of coatings to impart acid- or enzyme-resistance, delayed release, and other desirable release properties. A preferred method of employing such coatings is to directly coat a granulation of the desired pharmaceutical active ingredient. Such granules can be almost entirely active drug, or can be built up from nonpareil seeds, or by other techniques readily familiar to those of skill in the pharmaceutical manufacturing arts.
A difficulty is encountered in compressing such coated granules into commercially usable tablet products. Such granules can be formed into relatively soft tablets using low compression forces. However, the compressive forces required to produce a tablet which is sufficiently strong and cohesive to survive the stresses imposed by the subsequent film-coating process and commercial packaging and distribution inevitably result in fracture of the friable coating on a substantial percentage of the granules, resulting in uncontrolled rather than controlled release of the drug.
It has been known in the prior art to incorporate such coated granules into a tablet matrix which further incorporates a material which stabilizes the granules against compressive loads, such as disclosed in European Patent Application 196,546 of Becker. In that application, microcrystalline cellulose is used to form a matrix which effectively distributes compressive loads through the tablet as it is being formed, in effect bypassing the granules as load bearing elements of the tablet during compression.
A problem remains, however, in compressing granules formed from pharmaceutical agents whose physical properties cause the granule to be relatively smooth in surface texture or relatively waxy in overall granule texture. With such agents, such as divalproex sodium, the smooth granule surfaces make it difficult or impossible to achieve acceptable cohesion in tablets formed from the granules, even when very high compression forces are employed. Enteric and other coatings tend to make the surfaces of such smooth granules even smoother, as well as harder, further complicating this problem.
It is an object of this invention to provide a method of tableting drug granules having smooth surfaces which provides acceptable cohesiveness in the resulting tablets.
It is another object of this invention to provide granules which, although made from a material which is difficult to compress into tablets, can be made into tablets having acceptable cohesiveness.
It is a further object of this invention to provide granules and methods which accomplish the foregoing objects while avoiding fracture of any enteric or other coatings on the tablets These and other objects of the invention will be evident from the following disclosure.
Derwent abstract 72723A/41 (GB1598458) discloses a pharmaceutical tablet formulation containing enteric coated granules and microcrystalline cellulose. However, the tablet formulation also contains a polymer or waxy substance to which a granule-protecting activity is ascribed. The abstract in no way attributes the granule-protective action to the content of microcrystalline cellulose. Further, the microcrystalline cellulose is simply admixed in the tablet formulation.